Antidepressant drugs can modify cytotoxic action of temozolomide.

Cancer patients often require antidepressant treatment due to comorbid depressive disorder. However, recent studies have demonstrated that antidepressant drugs affect the efficacy of chemotherapy and promote progression of cancer. Apart from the main mood-improving effect, antidepressant drugs also produce analgesic, anxiolytic, hypnotic and pro-cognitive actions. Patients suffering from brain cancer constitute the greatest percentage of depressive cancer patients. However, vital safety and efficacy issues related to combined therapy with temozolomide, the first-line cytostatic in patients diagnosed with glioblastoma multiforme, and antidepressant drugs have yet to be addressed. The aim of the present studies was to evaluate the effect of three antidepressant drugs (imipramine, fluoxetine and tranylcypromine) on the cytotoxic efficacy of temozolomide on T98G cells, a human glioblastoma cell line. In our experiments, we used a complex experimental in vitro system to mimic the instability of a tumour's oxygen supply, thereby reproducing conditions that occur inside the tumour. The effect of the interaction between temozolomide and antidepressant drugs on viability, apoptosis and intensity of divisions of glioblastoma cells was evaluated under different oxygen conditions. The results of our studies demonstrated that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects.

Splenectomy attenuates the course of kidney ischemia-reperfusion injury in rats.

INTRODUCTION: Renal ischemia-reperfusion injury (IRI) initiates inflammatory response with synthesis of free oxygen radicals, chemokines, and cytokines which attract neutrophils and monocytes, which then differentiate into macrophages and dendritic cells, activating adaptive immune response. The spleen is the main source of both monocytes and lymphocytes. The aim of this study was to assess whether splenectomy performed before or upon IRI affects post-ischemic and long-term renal function. METHODS: Two weeks after right nephrectomy, the left kidney pedicle was clamped for 45 minutes in 24 rats. After the clip insertion, the spleen was removed in 12 animals and the remaining 12 rats underwent sham splenectomy. In the second experiment, splenectomy (n = 9) or sham procedure (n = 9) was performed simultaneously with right nephrectomy, 2 weeks before left kidney ischemia. The excretory function of the kidney was evaluated 48 hours and 7 days after ischemia. In the experimental model of chronic renal failure, 14 days before right nephrectomy, the prolonged 90-minute ischemia was induced in 32 rats with simultaneous splenectomy (n = 16) or sham procedure (n = 16). In long-term observation, the renal function and mortality rate was evaluated. RESULTS: Kidney function preservation was superior in rats that underwent splenectomy together with renal ischemia when compared to controls. This was further expressed with a 2 times lower mortality rate in splenectomized animals in 6 months observation after prolonged renal ischemia. Renoprotective effect was not observed when splenectomy was performed 2 weeks before IRI. CONCLUSIONS: The results suggest a detrimental influence of the spleen on the development of renal IRI.

Nephroprotective effect of pentoxifylline in renal ischemia-reperfusion in rat depends on the timing of its administration.

BACKGROUND: Renal ischemia-reperfusion injury (IRI) induces inflammatory reaction damaging kidney. Pentoxifylline (PTX) given before IRI attenuates inflammation and prevents ischemic acute kidney injury (iAKI). Given that in clinical settings IRI is not always predictable, we aimed to assess whether PTX administration during or shortly after IRI affects the course of iAKI in the rat. METHODS: In 58 male 10-week-old Sprague-Dawley rats, 14 days after right nephrectomy, a 45-minute clamping of solitary renal pedicle was conducted. PTX 100 mg/kg body weight or 0.9% NaCl 1 mL were given subcutaneously either 60 minutes before renal ischemia, 1 minute into ischemia, or 60 minutes after clamp release. Creatinine clearance (ClCr; mL/min/kg body weight), fractional excretions of sodium (FENa [%]) and potassium (FEK [%]), and urine protein/ClCr ratio (Uprot/ClCr [mg/1 mL ClCr]) at 48 hours after IRI were compared between PTX-treated animals and respective controls (Mann-Whitney U test). RESULTS: Kidney function was improved in rats given PTX before IRI compared with controls: ClCr 2.10 ± 0.44 versus 1.03 ± 0.18; FENa 0.16 ± 0.12 versus 0.84 ± 0.55; FEK 40.3 ± 13.0 versus 75.5 ± 17.9, respectively (all P < .001). There was no difference in proteinuria: Uprot/ClCr 0.004 ± 0.002 versus 0.004 ± 0.002. Conversely, the analyzed parameters did not differ between animals administered PTX during IRI and controls: ClCr 0.42 ± 0.34 versus 0.73 ± 0.43; FENa 2.98 ± 2.71 versus 3.16 ± 3.05; FEK 280.1 ± 155.7 versus 206.2 ± 154.1; and Uprot/ClCr 0.031 ± 0.029 versus 0.029 ± 0.031, respectively, nor between rats given PTX after IRI and controls: ClCr 0.29 ± 0.38 versus 0.40 ± 0.47; FENa 4.25 ± 3.55 versus 3.80 ± 3.94; FEK 284.9 ± 117.5 versus 243.0 ± 150.6; and Uprot/ClCr 0.044 ± 0.018 versus 0.055 ± 0.061, respectively. CONCLUSIONS: PTX given only before, and not at the time of renal ischemia or after reperfusion, alleviates subsequent iAKI in the rat. This implicates usefulness of PTX in the clinical settings of expected renal ischemia, like kidney transplantation, and suggests potential benefits of PTX in peritransplant period foremost with donor pretreatment.

Moclobemide exerts anti-inflammatory effect in lipopolysaccharide-activated primary mixed glial cell culture.

An increasing body of evidence indicates that glial activation and neuroinflammation play an important role in the pathogenesis of psychiatric and neurodegenerative diseases. Activated glial cells secrete various cytokines that influence neurotransmission, hypothalamus-pituitary-adrenal axis activity, neuronal plasticity and neurogenesis. It has been suggested that alterations in cytokine networks are involved in the mechanism of action of antidepressant drugs. Until now, only a few studies demonstrated that some tricyclic antidepressants and selective serotonin reuptake inhibitors reduced production of pro-inflammatory cytokines in brain glia cells. We have investigated for the first time whether the antidepressant, moclobemide (a reversible selective inhibitor of monoamine oxidase-A) has an influence on pro-inflammatory cytokines [interleukin (IL)-1ß and tumor necrosis factor (TNF)-α] and anti-inflammatory cytokine (IL-10) in primary rat mixed glial cell cultures stimulated by lipopolysaccharide (LPS). Our results showed that moclobemide used in a wide range of concentrations diminished LPS-stimulated IL-1ß and TNF-α mRNAs expression in cellular extracts and remarkably reduced the levels of both pro-inflammatory cytokines in culture medium. In opposite to this, the drug had no influence on IL-10 mRNA and slightly reduced IL-10 concentration. Moreover, moclobemide decreased LPS-stimulated translocation of NFκB p65 subunit into cellular nuclei. These results suggest that moclobemide exerts anti-inflammatory effect in the central nervous system because it affects the balance between pro- and anti-inflammatory cytokines (IL-1ß, TNF-α/IL-10) in primary mixed glial cell cultures.

Pentoxifylline augments fasting-induced nephroprotection in acute ischemic kidney injury in rats.

BACKGROUND: Prolonged fasting exerts anti-inflammatory effects, and pentoxifylline (PTX) has similar immunomodulating properties. OBJECTIVE: To compare the influence of feeding status and PTX administration on the course of acute ischemic kidney injury. MATERIAL AND METHODS: Seven days after right-sided nephrectomy and 7 days before renal ischemia, 44 male Sprague-Dawley rats were placed in individual cages with unlimited access to water. Rats were divided into 4 groups; groups Ia and Ib were fed with no limitations, and groups IIa and IIb were fasted for 32 hours before renal ischemia. Ninety minutes before clamping of the left kidney vascular pedicle, rats in groups Ib and IIb and those in groups Ia and IIa, respectively, were given either PTX subcutaneously, 100 mg per kilogram of body weight in 1 mL of 0.9% sodium chloride, or 0.9% sodium chloride only. Biochemical parameters of renal function were estimated at 48 hours after the ischemic event. RESULTS: Both fasting and PTX administration diminished the degree of ischemia-induced impairment of renal function. The combined effects were additive. CONCLUSIONS: Fasting and treatment with PTX during the preischemic period exerts additive nephroprotective effects in the setting of acute ischemic kidney injury. This finding may be useful in future practices of preservation and kidney transplantation.

Alterations in striatal neuropeptide Y system activity of rats with haloperidol-induced behavioral supersensitivity.

The study was conducted to determine whether the expression of behavioral supersensitivity induced by haloperidol (HAL) administered once daily (2 mg/kg i.p.) for 14 days is associated with the alterations in activity of neuropeptide Y (NPY) system in the striatum (caudate-putamen) and nucleus accumbens. Dopamine supersensitivity was tested by measurement of locomotor activity and stereotyped behavior after administration of the dopamine D2/D3 receptor agonist quinpirole (1 mg/kg i.p.) on day 1, 3 and 7 after HAL withdrawal. Neuropeptide Y-like immunoreactivity (NPY-LI) was determined in the striatum and nucleus accumbens isolated 6 h after quinpirole injection on day 1, 3 and 7 after the end of HAL treatment. NPY mRNA was quantified in these structures on day 7 after HAL withdrawal. HAL increased spontaneous locomotor activity and prevalence of rearing, grooming and head-down sniffing. At the same time, striatal NPY-LI increased progressively from the reduced level found on day 1 of haloperidol withdrawal. NPY mRNA remained unchanged. In saline-treated rats, quinpirole enhanced locomotion, rearing, and induced intense head-down sniffing and oral activity. These behavioral effects were accompanied by a decrease in striatal NPY-LI. NPY mRNA was slightly increased. HAL treatment altered response to quinpirole, namely it increased locomotion, intensified oral activity and reduced rearing and head-down sniffing. The second and the third quinpirole injection decreased NPY-LI levels. NPY mRNA was unchanged. In the nucleus accumbens, apart from a decrease in NPY-LI on day 1 after the last haloperidol dose, the level of NPY-LI and NPY mRNA in any experimental group did not differ from the control value. The presented results suggest that the alterations in the activity of the striatal but not nucleus accumbens NPY system contribute to adaptive changes induced by long-term haloperidol treatment and may be of significance to the motor hyperactivity induced by intermittent stimulation of postsynaptic dopamine D2 receptors.

Increased striatal neuropeptide Y immunoreactivity and its modulation by deprenyl, clonidine and L-dopa in MPTP-treated mice.

The aim of this study was to evaluate the effect of MPTP (2 x 45 mg/kg s.c., 20 h apart) on striatal neuropeptide Y-like immunoreactivity (NPY-LI) in C57BL/6 mice. NPY-LI markedly increased 2 weeks after MPTP but it remained unchanged after 24 h, 1 or 6 weeks. The increase in NPY-LI was accompanied by depletion of dopamine (-80%), DOPAC (-70%), 3-MT (-44%) and HVA (-52%). L-Deprenyl completely prevented the MPTP-induced NPY-LI increase, neurodegeneration of the striatal dopamine system and motor dysfunction. Clonidine attenuated the neurotoxin effect on NPY-LI and dopaminergic neurons. L-dopa/carbidopa protected NPY neurons against MPTP but slightly enhanced MPTP-induced decrease in the levels of dopamine and its metabolites. The relationship between changes in NPY-LI and dopamine and serotonin metabolism determined by HPLC was discussed. The results further extend the range of MPTP-elicited modifications in striatum and demonstrate that drugs with antiparkinsonian activity can protect NPY neurons against MPTP toxicity.

Effects of haloperidol and clozapine on neuropeptide Y-like immunoreactivity in the nucleus accumbens and striatum of rats pretreated with psychostimulants.

It has been shown that the synthesis, release and levels of neuropeptide Y (NPY), a peptide linked to the dopamine system, are altered by stimulants with psychotomimetic properties and by antipsychotic drugs. This study was designed to evaluate the effect of 3-day haloperidol (HAL) (2 mg/kg i.p.) or clozapine (CLOZ) (25 mg/kg i.p.) treatment on neuropeptide Y-like immunoreactivity (NPY-LI) in nucleus accumbens and striatum (caudate-putamen) in rats pretreated with d-amphetamine or phencyclidine. D-amphetamine (5 mg/kg s.c. twice daily for 6 days and once on day 7) and phencyclidine (10 mg/kg i.p. once daily for 2 days and 15 mg/kg once on day 3) induced marked stereotypy with different symptomatology. Stereotypy is thought to resemble psychosis-related behavior. The first dose of either HAL or CLOZ was given 3 or 2h after the final d-amphetamine or phencyclidine injection, respectively. The control groups were injected with either saline alone, saline instead of psychostimulants, which was followed by antipsychotics, or psychostimulants followed by saline. Rats were sacrificed 24h after antipsychotics or 72 h after the last psychostimulant dose. Both psychostimulants similarly reduced nucleus accumbens and striatal NPY-LI. In saline-pretreated rats, HAL and CLOZ decreased nucleus accumbens NPY-LI, but only HAL decreased striatal NPY-LI. In both the structures examined the effects of HAL and d-amphetamine on NPY-LI were additive. HAL slightly enhanced but CLOZ reversed the phencyclidine-induced decrease in accumbens NPY-LI. The present study has shown that HAL and CLOZ produce different effects on nucleus accumbens and striatal NPY-LI in d-amphetamine or phencyclidine pretreated rats, and it suggests that these effects are related particularly to the dopaminergic and glutamatergic systems whose activities were altered by psychostimulants.

Neuropeptide Y in obese women during treatment with adrenergic modulation drugs.

BACKGROUND: The aim of the study is the assessment whether weight loss treatment with adrenergic modulation drugs modifies neuropeptide Y (NPY) plasma concentration in obese women. MATERIAL AND METHODS: 13 obese women (BMI 38.3 +/- 4.4) were tested before and subsequently 10 and 20 days after weight loss treatment. The treatment consisted of a very low caloric diet of 400 kcal (1670 kJ) daily combined with ephedrine with caffeine (E + C) or ephedrine with caffeine and yohimbine (E + C + Y) administered for 10 days using the cross-over method. The patients underwent physical examination, including heart rate and blood pressure measurements, spectral heart rate variability (HRV) at rest and after 3 minute handgrip and a 15 minute cycloergometer exercise at 75 W. All the above mentioned tests were carried out thrice in each patient. In 13 obese patients and in 6 control women plasma NPY concentrations were determined by a specific radioimmunoassay using rabbit anti-NPY antiserum and a standard synthetic porcine NPY (Peninsula Lab.). RESULTS: Plasma NPY concentrations were significantly lower in the obese persons compared with the control group. During weight loss treatment with adrenergic modulation drugs no changes in plasma NPY were found at rest and after physical exercise. Also no differences in HRV indices were observed. CONCLUSIONS: 1. Low plasma NPY concentration observed in obesity may be a contraregulatory factor that could prevent further weight increase. 2. Weight reduction treatment did not affect plasma NPY concentration and cardiovascular response to physical exercise. 3. The doses of adrenergic modulation drugs used in our study did not induce any serious side effects, and were so low that no change of plasma NPY concentration and cardiovascular responses were observed at rest.

Pharmacological studies on the monoaminergic influence on the synthesis and expression of neuropeptide Y and corticotropin releasing factor in rat brain amygdala.

Our earlier findings concerning the 6-OHDA lesion suggested dopaminergic regulation of neuropeptide Y (NPY) and corticotropin releasing factor (CRF) synthesis and expression in amygdala neurons. On the other hand, some other studies indicated that not only dopamine, but also other monoamines may modulate peptidergic neurons. Therefore the present study examined the effect of pharmacological deprivation of monoaminergic influences on NPY and CRF neurons in rat brain amygdala by means of in situ hybridization and immunohistochemical methods. It was found that NPY mRNA expression in the amygdala decreased after 24h blockade of dopaminergic D1 and D2 receptors, by haloperidol or SCH23390. At the same time the NPY-peptide expression measured immunohistochemically was not significantly changed. A prolonged, 14-day, blockade of dopaminergic receptors by haloperidol induced an opposite effect, an increase in NPY mRNA expression. Impairment of the serotonergic transmission by blockade of 5-HT synthesis using p-chlorophenylalanine, as well as attenuation of the noradrenergic transmission by NA depletion from terminals by DSP4, did not significantly change NPY mRNA expression or the mean number of NPY-immunoreactive neurons in the amygdala. Only a decrease in the staining intensity observed as a decreased number of darkly stained neurons was found after both compounds. Neither the dopamine receptor blockade nor the impairment of serotonergic or noradrenergic transmission changed CRF mRNA or the peptide expression in the amygdala. The obtained results indicate that in rat brain amygdala, of all the monoamines, dopamine seems to be the most important modulator of NPY biosynthesis and expression. The effect of blockade of dopaminergic receptors is biphasic: first it induces a decrease and then - after prolonged treatment an increase in NPY mRNA. Serotonergic and noradrenergic systems in the amygdala seem to be connected with regulation of NPY release rather than the biosynthesis.

Effect of substituted benzamides on feeding and hypothalamic neuropeptide Y-like immunoreactivity (NPY-LI) in rats.

The study was conducted: (i) to evaluate the effects of three substituted benzamides on feeding behaviour in rats with free access to food and in those with access to food limited either to the light or to the dark phase of the diurnal cycle; and (ii) to determine whether the hypothalamic neuropeptide Y (NPY) system is involved in the action of these drugs on feeding. In free-feeding rats, a single dose of eticlopride (1 mg/kg, i.p.) or raclopride (1 mg/kg, i.p.) decreased 24-h food intake, whereas remoxipride (3 mg/kg, i.p.) produced no effect. Single doses of eticlopride and raclopride but not of remoxipride decreased hypothalamic neuropeptide Y-like immunoreactivity (NPY-LI). Eticlopride administered once daily for 14 days decreased both food intake and hypothalamic NPY-LI. When given for 14 days, raclopride and remoxipride decreased food intake in rats with access to food in the dark (19.00-07.00) but not in thelight (07.00-19.00) phase of the diurnal cycle; both these compounds decreased hypothalamic NPY-LI only in the former group of rats. The results suggest that the effects of substituted benzamides on feeding behaviour depend on the drug and the time of administration and that these effects are related to the altered function of the hypothalamic NPY system.

[The role of neuropeptide Y in anxiety]. / Rola neuropeptydu Y w leku.

Neuropeptide Y (NPY), one of the most abundant peptides in the mammalian brain, is implicated in the control of many physiological processes. It is also suggested the involvement of NPY in several neuropsychiatric illnesses. This review summarizes the present knowledge concerning the role of NPY in anxiety and discusses probable sites and receptors involved in the anxiolytic-like effect of NPY as well as interactions between the NPY and corticotropin-releasing factor (CRF) systems. The possible role of the NPY system in human psychopathological conditions associated with anxiety is also reviewed. Based on our data, we suggest that the NPY system is involved in antianxiety effects of diazepam and buspirone.

Conditioned fear-induced changes in neuropeptide Y-like immunoreactivity in rats: the effect of diazepam and buspirone.

The study aimed to investigate the influence of conditioned fear, produced in the passive avoidance test, on neuropeptide Y-like immunoreactivity (NPY-LI) and the effect of anxiolytics on NPY-LI in frightened rats. Rats avoided the dark chamber, where they were previously subjected to electric footshock, and they exhibited increased numbers of defecations and gastric ulcers. Moreover, they showed increased NPY-LI in the amygdala, nucleus accumbens and hypothalamus, and decreased NPY-LI in the frontal cortex. Diazepam (1 or 3 mg/kg) and buspirone (1.5 or 5 mg/kg) dose-dependently inhibited passive avoidance and decreased the numbers of defecations, and they also decreased the number of gastric ulcers. Diazepam reversed while buspirone only attenuated the fear-induced changes in NPY-LI in all regions studied. In the amygdala, the effect of diazepam was dose-dependent. The effect of diazepam on both behaviour and NPY-LI was antagonized by flumazenil (15 mg/kg). Apart from supporting the role of the NPY system in fear and anxiety, the results of this study suggest that NPY is involved in the anxiolytic effects of diazepam and buspirone and that the effect of diazepam is mediated by benzodiazepine receptors.

Effect of haloperidol treatment on immunoreactive neuropeptide Y secretion into lateral cerebral ventricle of rats.

The study aimed to evaluate the effect of acute and 14-day haloperidol treatment (2 mg/kg ip) on release of neuropeptide Y-like immunoreactivity (NPY-LI) in non-anesthetized, freely moving rats by means of push-pull perfusion of the lateral cerebral ventricle. Twenty four hours after a single haloperidol injection NPY-LI release decreased by 15% (p < 0.05). No alterations were detected after 14-day haloperidol treatment. The study has confirmed that haloperidol alters the activity of neuropeptide Y system in the rat brain and suggested that acute haloperidol treatment inhibits the activity of the neuropeptide Y system at least in some brain structures surrounding the cerebral ventricles. The presented results have been discussed in view of our previous findings describing the haloperidol-induced changes in NPY-LI and NPY mRNA levels in the rat brain.

Role of corticotropin-releasing factor (CRF) in anxiety.

Apart from its regulatory role in release of adrenocorticotropic hormone (ACTH) and beta-endorphin, corticotropin-releasing factor (CRF) is implicated in behavioral functions. This review summarizes the present knowledge of the role of CRF in anxiety and discusses probable sites and receptors involved in the anxiogenic-like effect of CRF as well as possible interactions between the CRF system and other peptides. The role of the CRF system in human psychopathological conditions associated with anxiety is also reviewed. Based on the available literature, we suggest that the CRF system may interact with antianxiety drugs and that this interaction may be of importance in the development of anxiety induced by ethanol or cocaine withdrawal.

Differential behavioural effect of quinpirole in neuroleptic-pretreated rats - role of alpha(1)-adrenoceptor.

This paper presents the effect of 14-day intraperitoneal (i.p.) neuroleptic treatment on the behavioural response of Wistar rats to (-)-quinpirole hydrochloride (3 mg/kg, i.p.) administered 24 h after the last neuroleptic dose. Chlorpromazine hydrochloride (10 mg/kg), haloperidol (2 mg/kg) or (+/-)-sulpiride (100 mg/kg) increased the effect of quinpirole; however, there were qualitative and quantitative differences between the neuroleptics. Chlorpromazine and haloperidol, but not sulpiride, pretreatment enhanced quinpirole-induced locomotor hyperactivity. Prazosin (0.5 mg/kg, i.p. ) given to chlorpromazine-treated rats 1 h before quinpirole attenuated the quinpirole-induced hyperlocomotion. In chlorpromazine-pretreated rats, quinpirole elicited defensive aggressive behaviour with vocalization, copulatory attempts, intense rearing and head-down sniffing. When prazosin was given before quinpirole, head-down sniffing and object-directed oral activity were mainly observed. In haloperidol-pretreated rats, quinpirole induced intense head-down sniffing, rearing, grooming and object-directed oral activity. In sulpiride-pretreated rats, quinpirole induced intense head-down sniffing, grooming and object-directed oral activity. The results of the study suggest that differences in the behavioural expression of dopamine D(2) receptor supersensitivity induced by neuroleptics may be, at least in part, caused by concurrent stimulation of alpha(1)-adrenoceptors.

Clozapine decreases neuropeptide Y-like immunoreactivity and neuropeptide Y mRNA levels in rat nucleus accumbens.

The aim of this study was to evaluate the effect of acute, subchronic (14 days) and chronic (28 days) intraperitoneal (i.p.) administration of clozapine (10 or 25 mg/kg) on neuropeptide Y (NPY) system activity in the nucleus accumbens of the rat. NPY-like immunoreactivity (NPY-LI) decreased 24 h after subchronic clozapine while NPY mRNA after both acute and subchronic clozapine treatment. NPY-LI levels were also reduced 8 days after cessation of chronic lower-dose treatment. Subchronic (14 days) administration of the 5-HT2A antagonist ketanserin (1 mg/kg i.p.) or the dopamine D2/D3 antagonist (+/-) sulpiride (100 mg/kg i.p.) reduced NPY-LI levels, whereas the dopamine D1-like antagonist SCH 23390 (0.5 mg/kg i.p.), dopamine D4 antagonist L-745,870 (1 mg/kg per os), and alpha1-adrenergic antagonist prazosin (0.2 mg/kg i.p.) had no effect. There were no significant differences between the ketanserin-induced decrease in NPY-LI levels and the effects of the following two-drug combinations: ketanserin and SCH 23390, ketanserin and L-745,870, and ketanserin and prazosin. The study has shown that clozapine reduces NPY system activity in the rat nucleus accumbens. It seems that the action of clozapine is partly mediated by blockade of 5-HT2A and D2/D3 dopaminergic receptors.

Interactions between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis.

The aim of this paper is to review the present knowledge of interactions between the neuropeptide Y (NPY) system and the hypothalamic-pituitary-adrenal (HPA) axis. On the basis of in vitro and in vivo studies of various animal species, we review the effects of NPY on all levels of HPA axis activity. We also describe the effects of glucocorticosteroids on the NPY system in the hypothalamus, including interactions between glucocorticosteroids and insulin. On the basis of available literature, we discuss the role of these interactions in the control of food intake and in the pathogenesis of obesity.

Effects of acute or long-term treatment with chlorpromazine, haloperidol or sulpiride on neuropeptide Y-like immunoreactivity concentrations in the nucleus accumbens of rat.

The effects of acute, subchronic ( 14 days) or chronic (28 days) intraperitoneal (i.p.) administration of chlorpromazine (2 or 10 mg/kg), haloperidol (0.5 or 2 mg/kg) or sulpiride (50 or 100 mg/kg) on the neuropeptide Y (NPY) system in the rat nucleus accumbens were studied. NPY-like immunoreactivity (NPY-LI) decreased in a dose- and time-dependent manner, and was the lowest after haloperidol. NPY-LI levels increased 8 days after withdrawal of chronic drugs treatment. Acute administration of haloperidol reduced NPY mRNA, while Subchronic treatment did not change it. Subchronic i.p. administration of the dopamine D1-like antagonist SCH 23390 (1 mg/kg) reduced NPY-LI levels but the alpha1-adrenergic antagonist prazosin (0.2 mg/kg) had no effect. The effect of sulpiride coadministered with SCH 23390 was greater than that of SCH 23390 alone, while prazosin coadministered with sulpiride insignificantly reduced the effect of sulpiride. The dopamine D2/D3 agonist quinpirole given as a single injection (3 mg/kg) did not alter NPY-LI content by itself but antagonized the chlorpromazine-induced decrease and attenuated the haloperidol-induced decrease. Our findings indicate that the accumbens NPY system is markedly affected by the antipsychotics studied, and suggest that their effects may be in part mediated by blockade of D2-like (D2, D3) and D1 dopaminergic receptors.

Diazepam and buspirone alter neuropeptide Y-like immunoreactivity in rat brain.

Neuropeptide Y-like immunoreactivity (NPY-LI) was investigated in naIve Sprague-Dawley rats subjected to acute, subchronic (7 days) or chronic (21 days) intraperitoneal treatment with diazepam (1 or 3 mg/kg once daily) or buspirone (1.5 or 5 mg/kg twice daily). NPY-LI was determined by radioimmunoassay in the amygdala, nucleus accumbens, hypothalamus and frontal cortex 24 h after the last dose of the drugs. Amygdala NPY-LI decreased after acute diazepam (3 mg/kg) or buspirone (1.5 mg/kg) and increased after subchronic treatment with both doses of diazepam and after chronic buspirone (1.5 mg/kg) treatment. Both diazepam and buspirone given in subchronic and chronic doses decreased NPY-LI levels in the nucleus accumbens. Hypothalamic NPY-LI changed only after chronic treatment: it decreased after diazepam and increased after buspirone (5 mg/kg). NPY-LI content in the frontal cortex decreased after subchronic diazepam (3 mg/kg) treatment and slightly increased after buspirone. The study has shown that both diazepam and buspirone affect NPY-LI levels in rats. These results suggest that the NPY system in the amygdala and nucleus accumbens is implicated in the anxiolytic effects of the drugs studied.